tbuckley/cabot-search huggingface dataset:
Abstract LB340: Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer
Authors: Shuang Qu, Jiafan Wang, Meng Jia, Hongwei Liang, Yuan Liu, Ke Zen
Journal: Cancer Research (2023)

Abstract Red blood cells (RBCs) have been widely used in delivering various drugs including cancer antigens. However, due to their inherent biocompatibility and low immunogenicity, RBC-based tumor antigen delivery often fails to initiate anti-tumor immunity and results in lower clinical efficacy of cancer vaccines. Here we report that tumor antigen-encapsulated RBCs can be rapidly transformed to spur cells which have much higher immunogenicity. Compared to normal RBCs, spur cells display a defused surface CD47 pattern with a lower affinity to SIRPα, and thus can be rapidly engulfed by activated macrophages and dendritic cells. The tumor antigen-loaded spur cells elicit high antigen responses both in vitro and in vivo. In combination with the SHP-1 inhibitor, spur cell-delivered KRASG12D antigenic peptides markedly suppress tumor growth in KRASG12D spontaneous mouse lung cancer model. In addition, a specific T cell population targeting the KRASG12D mutated peptide antigen is detected in cancer-survival mice. Our study thus has developed spur cell-delivered cancer neoantigen as an effective cancer vaccine. Citation Format: Shuang Qu, Jiafan Wang, Meng Jia, Hongwei Liang, Yuan Liu, Ke Zen. Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB340.
Abstract LB361: Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death
Authors: Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, David R. Tong, Aleksandar Z. Obradovic, Ana M. Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol L. Prives
Journal: Cancer Research (2023)

Abstract Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches. Citation Format: Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, David R. Tong, Aleksandar Z. Obradovic, Ana M. Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol L. Prives. Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB361.
Abstract CT249: A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors
Authors: Marwan Fakih, Davendra P. Sohal, Navid Hafez, Jordan D. Berlin, Kimberly Hari, Ovid C. Trifan
Journal: Cancer Research (2023)

Abstract Background: TOS-358 is an orally available, highly selective covalent inhibitor of PI3Kα capable of achieving a deep and durable inhibition of PI3K-AKT signaling with virtually no off-target effects. In patient-derived xenograft models, TOS-358 has shown anti-cancer activity in several different tumor types including breast, colorectal, gastric, head and neck, bladder, and esophageal cancer, and its’ activity was superior to non-covalent compounds targeting PI3Kα. Administered at the equivalent dose, TOS-358 has shown a good safety profile in 28-day repeat dose toxicity studies in rats and dogs. Methods: The TOS-358-001 study is a multicenter dose escalation (phase 1) and dose expansion (phase 1b) clinical study evaluating the safety, tolerability, and preliminary efficacy of TOS-358. Eligible subjects are adults with one of protocol-defined tumor types, known PIK3CA mutation or amplification, adequate organ function, ECOG performance status 0 or 1, available archived or fresh tumor tissue for PIK3CA mutation detection and no prior treatment with PI3K, AKT or mTOR inhibitors (except subjects with breast cancer). The phase 1 portion of the study follows a 3+3 dose escalation design and is intended to determine the minimum effective dose (MED) and the maximum tolerated dose (MTD) of TOS-358 when administered orally on a once daily (QD) or a twice daily (BID) schedule, and the recommended phase 2 dose (RP2D). Cohort expansions at the MTD and MED to support the RP2D selection are planned. The phase 1b portion of the study will enroll subjects with tumor PIK3CA mutations or amplifications in several tumor-specific cohorts (colorectal, gastric, non-small cell lung, breast, squamous cell carcinoma of the head and neck, urothelial and select gynecological cancers) to further assess the safety and tolerability of TOS-358 and to evaluate the initial efficacy of the investigational agent. Enrolment to the study commences in US with European sites planned to open later in 2023. Clinical trial information: NCT05683418. Citation Format: Marwan Fakih, Davendra P. Sohal, Navid Hafez, Jordan D. Berlin, Kimberly Hari, Ovid C. Trifan. A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT249.
Abstract CT232: Safety, efficacy, and tolerability of FHND9041 capsules as first-line treatment in patients with EGFR sensitive mutations or second/third-line treatment in patients with T790M+ advanced non-small cell lung cancer (NSCLC): results from a phase I/II single-arm, multi-center, open-label study
Authors: Yongqiang Zhu, Minghong Shang, Jia Wang, Nong Yang, Xiaorong Dong
Journal: Cancer Research (2023)

Abstract Background: FHND9041 is a third-generation EGFR inhibitor independently developed by Nanjing Chuangte Pharmaceutical Technology Co., Ltd. It irreversibly binds to EGFR protein, and demonstrates strong inhibitory effect on EGFR T790M mutations as well as EGFR sensitive mutations. This is the first single-arm, multi-center, open-label phase I/II study of FHND9041 capsule, which evaluates the safety, tolerability and preliminary efficacy of FHND9041 capsule in initial treatment of NSCLC with EGFR sensitive mutations or treatment of T790M+ advanced NSCLC who progressed after prior EGFR-TKI therapy. Methods: 124 subjects tested for EGFR mutations and eligible for evaluation were randomized to dose groups of 40 mg, 80 mg (first-line treatment or second/third-line treatment with T790M+), 120 mg and 180 mg. The primary endpoint is objective response rate (ORR), and key secondary endpoints are progression-free survival (PFS), disease control rate, duration of response, and safety. Results: The ORR of FHND9041 capsule 80 mg (recommended phase 2 dose, RP2D) is 71.43% in patients newly diagnosed of NSCLC with EGFR sensitive mutations, and 63.64% in patients with T790M+ NSCLC who had progressed after prior EGFR-TKI therapy. No DLT occurred in all dose groups, 40 mg, 80 mg and 120 mg, which demonstrated satisfactory tolerability and safety of FHND9041. Detailed efficacy data of each dose group is shown in the table below. Conclusion: FHND9041 capsule 80 mg shows significant antitumor activity with favorable efficacy and safety profile in patients for both initial treatment and treatment of T790M+ NSCLC who progressed after prior therapy. For futher research of the capsule, a multicenter, randomized, positive-controlled phase III clinical research is ongoing with recommended dose of 80 mg. Group Dosage(mg) Evaluable Subjects(n) ORR% Second/Third-line T790M+ 40mg 3 33.33 80mg 39 63.64 120mg 42 58.33 180mg 3 100.00 First-line 80mg 37 71.43 Citation Format: Yongqiang Zhu, Minghong Shang, Jia Wang, Nong Yang, Xiaorong Dong. Safety, efficacy, and tolerability of FHND9041 capsules as first-line treatment in patients with EGFR sensitive mutations or second/third-line treatment in patients with T790M+ advanced non-small cell lung cancer (NSCLC): results from a phase I/II single-arm, multi-center, open-label study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT232.
Abstract LB351: A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer
Authors: Alex M. Jaeger, Andrew Weeden, Anika Ali
Journal: Cancer Research (2023)

Abstract Antigen presentation is a fundamental component of cancer immunity. Cytotoxic CD8+ T cells, the primary mediators of cell killing, recognize peptide antigens presented in the context of Major Histocompatibility Complex Class I (MHC-I). MHC-I presents an astoundingly diverse array of peptides, collectively known as the immunopeptidome. The biosynthesis of the immunopeptidome, which integrates gene expression, protein synthesis, and proteolytic processing, is not well understood. Additionally, most studies interrogating the immunopeptidome use cultured cells in vitro, which lack physiologically relevant stimuli. In contrast, in vivo studies utilize bulk tumor or tissue lysates, in which heterogeneous cell mixtures obscure the ability to understand cell type or disease specific patterns of antigen presentation. The technical limitations have hampered our understanding of the cancer immunopeptidome in physiologically relevant tumor microenvironments in vivo. Here we present a novel genetically engineered mouse model (GEMM) of cancer, that includes KrasLox-Stop-Lox-G12D; p53fl/fl; a Cre conditionally tagged MHC-I (KbStrep), and a Cre conditionally tagged ribosome (Rpl22HA/HA), termed the “KP/RiboMHC” mouse model. The KP/RiboMHC model enables simultaneous purification of ribosomes and peptide MHC complexes to functionally interrogate translational dynamics and antigen presentation in vivo. We developed optimized workflows to perform simultaneous ribosome profiling and immunopeptidomics from lung and pancreas cancer cell lines in vitro and specifically from malignant cells in vivo. Thus, the KP/RiboMHC model provides an unprecedented opportunity to ask fundamental questions regarding the influence of physiological stimuli in the tumor microenvironment on the biosynthesis of the immunopeptidome. Insights gained using this mouse will pave the way forward for the development of context specific, peptide-centric cancer immunotherapies. Citation Format: Alex M. Jaeger, Andrew Weeden, Anika Ali. A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB351.
Abstract LB006: Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions
Authors: Matias Kinnunen, Xiaonan Liu, Kari Salokas, Salla Keskitalo, Markku Varjosalo
Journal: Cancer Research (2023)

Abstract Chromosomal translocations creating fusion genes are among the most common mutation class of known cancer genes, and they have long been identified as driver mutations in certain types of cancer. Recently, oncogenic fusion genes (oncofusions, OFs) have been found in many hematological and solid tumors, demonstrating that translocations are a common cause of malignancy. The frequency of recurrent gene fusions varies depending of the specific type of cancer, but currently identified translocations are estimated to drive up-to 20% of cancer morbidity. In many occasions the oncofusion is the sole driver of oncogenesis when present and certain oncofusion pairs are typically found in one or few specific cancers. ETV6-NTRK3 (EN) oncofusion, is a product of the chromosomal t(12; 15)(p13; q25) translocation, which fuses the N-terminal SAM (sterile alpha motif) domain of ETV6 to the C-terminal protein tyrosine kinase domain of NTRK3 (also known as TrkC). EN is expressed from the ETV6 promoter in the fused chromosome 15. The ETV6 promoter is generally more active, than NTRK3 promoter, and causes EN fusions to be expressed more highly in several tissues and especially in bone marrow and salivary glands. ETV6 forms fusions with many kinases, which are found in hematological malignancies and solid tumors. Except for ETV6-NTRK3, other ETV6-kinase fusions are reported in either hematological or solid malignancies and ETV6-NTRK3 further distinguishes itself by being also reported in several subtypes in both cases. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the EN fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer. Citation Format: Matias Kinnunen, Xiaonan Liu, Kari Salokas, Salla Keskitalo, Markku Varjosalo. Interactome analysis identifies signaling pathways activated by ETV6-NTRK3 oncogenic gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB006.
Abstract LB346: Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients
Authors: Elena Montauti, Ole Haabeth, Chris Rae, Samuel Deutsch, Lawrence Fong, David Oh
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer (PC) remains refractory immune checkpoint therapies (CPT) despite having an FDA-approved cancer vaccine. PC is known to have a low mutation burden resulting in low level of neoantigens, so shared tumor associated antigens (TAAs) and translocations presumably represent a dominant source of antigens in this disease. While PC is thought to be a poorly immunogenic tumor, the frequency and breadth of tumor antigen reactivity in PC patients is unclear. Methods: We utilized novel programmable immunogenic mRNA nanoparticle platform and created formulations encoding a range of full-length prostate TAAs (TAAmRNA) to systemically study T cell immune responses to across a range of TAAs in PC patients. We administered 8 PC TAAmRNAs (NY-ESO-1, HK2, STEAP1, TMPRSS2-ERG, PAP, PSA, PSCA and PSMA) to in-vitro cultured peripheral blood mononuclear cells (PBMC) from 43 treatment-naïve localized PC patients compared to 17 age-matched non-cancer control patients. We assessed upregulation of early T cell activation markers and interferon-gamma (INFg) cytokine production through flow cytometry and ELISPOT, respectively. Results: 20% of PC patients possessed TAA-specific CD8+ T cell responses to at least one antigen. NY-ESO-1, HK2 and TMPRSS2-ERG had the highest T cell recall responses at an average of 35%, with NY-ESO-1 demonstrating the strongest responses per patient. Of the patients that respond to any given TAA, 47% of patients responded to three or more antigens, with 11% of PC patients responding to all TAAs. PC patients also showed heightened production of IFNg, with 35% of patients showing pan-responsiveness to three or more antigens. Particularly, HK2 stimulated the highest levels of INFg production. These levels of responsiveness are not seen in the control cohort. Conclusions: Encapsulated mRNA nanoparticles can be used to systematically map antigen reactivity across a cohort of cancer patients and reveal frequent pan-responsiveness to multiple TAAs in what has considered to be an immunologically cold cancer These results also reveal a hierarchy in immunogenicity of candidates that can enable future vaccine development. Continual efforts to assess the immunogenicity of shared PC TAAs in more advanced disease, and how patient responses to TAAs are modulated by immunotherapies, can aid in refining combinatorial therapies for PC. Citation Format: Elena Montauti, Ole Haabeth, Chris Rae, Samuel Deutsch, Lawrence Fong, David Oh. Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB346.
Abstract LB341: Single-cell CRISPR screens in primary human T cells identify regulators of Th2 cell skewing
Authors: Anke Loregger, Johanna Irnstorfer, Nicole Untermoser, Nikola Vinko, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer
Journal: Cancer Research (2023)

Abstract CRISPR screens have become the primary discovery engine in modern biology. However, many screening workflows are still performed in cancer cell lines and coupled to simplistic read-outs such as cellular fitness. At Myllia Biotechnology, we combine CRISPR screening with single-cell RNA sequencing, leveraging two transformative technologies to enable genetic screening for complex phenotypes. We utilize the CRISPR screening workflow to map the impact of thousands of genetic perturbations on the global transcriptome at single-cell resolution. Our powerful approach has broad applications in identifying novel drug targets or elucidating unknown mechanisms of actions of drugs. Primary human T cells are currently of great interest in the scientific community. They are not only key players in autoimmunity and other inflammatory diseases, but also represent attractive targets for immunotherapy of cancer. To enable the discovery of novel targets, we built a workflow that utilizes CD4+ T cells from peripheral blood and allows functional genomic screens in these cells. Upon activation, naïve CD4+ T cells proliferate and differentiate into specific T helper cell subsets, such as Th1, Th2, or Th17 cells. Here, we present data of an experiment in which we screened for regulators of T helper cell differentiation and skewed cells towards the Th2 subset. We aimed to identify genes whose knockout boosts or attenuates the ability of primary naïve CD4+ T cells to become Th2 cells. Th2 cells support the humoral immune response, and their dysfunction has been linked to inflammatory diseases, including asthma. In our screen, the different T cell subsets could be captured using curated transcriptomic signatures. Importantly, several gene KOs introduced in a pooled fashion using CRISPR/Cas9 accumulated in distinct subpopulations, suggesting that these genes regulate the differentiation of naïve T cells into the various T helper cell subsets. Overall, our pooled screening approach in primary human T cells allows for novel insights in the plasticity of T cells and identifies genes that could serve as drug targets in autoimmunity, inflammation and immuno-oncology. Citation Format: Anke Loregger, Johanna Irnstorfer, Nicole Untermoser, Nikola Vinko, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer. Single-cell CRISPR screens in primary human T cells identify regulators of Th2 cell skewing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB341.
Abstract LB005: Insights of renal cell carcinoma from multiomic perspective
Authors: Aron Bartha, Zsuzsanna Darula, Gyongyi Munkacsy, Eva Klement, David Fenyo, Peter Nyirady, Balazs Gyorffy
Journal: Cancer Research (2023)

Abstract Introduction: Clear cell renal carcinoma is the most frequent form of renal malignancy, with an increasing incidence rate worldwide. In this study we used a multi-omic approach to differentiate normal and tumor tissues in clear cell Renal Cell Carcinoma (ccRCC). Methods: Using transcriptomic data of patients with malignant and adjacent normal tissue samples from gene chip and RNA-Seq cohorts, we identified the top genes over-expressed in ccRCC. We collected surgically resected ccRCC specimens to further investigate the transcriptomic results on the proteome level. The differential protein abundance was evaluated using targeted mass spectrometry (MS). Results: We assembled a database of more than 600 renal tissue samples from NCBI GEO and TCGA and used these to uncover the top genes with higher expression in ccRCC. For protein level analysis 162 malignant and normal kidney tissue samples have been acquired. The most consistently upregulated genes were IGFBP3, PLIN2, PLOD2, PFKP, VEGFA, and CCND1 (p&amp;lt;1E-05 for each gene). Mass spectrometry further validated the differential protein abundance of these genes (IGFBP3, p = 7.53E-18; PLIN2, p = 3.9E-39; PLOD2, p = 6.51E-36; PFKP, p = 1.01E-47; VEGFA, p = 1.40E-22; CCND1, p= 1.04E-24). We also identified proteins correlating with overall survival. Conclusions: We used transcriptomic and proteomic data to identify a minimal panel of proteins highly specific for clear cell renal carcinoma tissues. The introduced gene panel could be used as a promising tool in the clinical setting. Citation Format: Aron Bartha, Zsuzsanna Darula, Gyongyi Munkacsy, Eva Klement, David Fenyo, Peter Nyirady, Balazs Gyorffy. Insights of renal cell carcinoma from multiomic perspective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB005.